This project is designed to assess the roles of muscarinic and nicotinic cholinergic mechanisms that modulate P50 auditory sensory gating in schizophrenia. We have previously combined recording the P50 waveform of the auditory evoked potential (AEP) with a conditioning-testing paradigm used to assess the strength of inhibitory neuronal pathways. Normal controls show a significant decrement of the AEP P50 waveform in response to the second of two closely paired clicks. Both unmedicated and medicated schizophrenic subjects show less decrement, indicating, a deficit in P50 auditory gating. About half of all first-degree relatives of schizophrenic patients have as a trait, a similar deficit in P50 auditory sensory gating. By studying the P50 auditory sensory gating deficit in first degree relatives of identified patients, we can elucidate the mechanisms underlying the inherited deficit in P50 auditory sensory gating without having to control for the effects of neuroleptics and anticholinergic medications that arc commonly used to treat schizophrenic patients. In an animal model, blocking nicotinic cholinergic neuronal transmission to the hippocampus impaired auditory sensory gating. This deficit was reversed by treatment with nicotine. In a preliminary study, we found that oral nicotine transiently enhanced P50 gating in first-degree relatives with impaired P50 gating. The relative importance of muscarinic versus nicotinic modulation of P50 auditory gating in human subjects has not been established. However, elucidating the relative importance of the two mechanisms would greatly enhance our understanding of a sensory gating deficit associated with schizophrenia, and perhaps point the way toward new pharmacologic approaches in treating schizophrenia. In this study we will study 3 groups of subjects- normal controls with no family history of mental illness, nongating first-degree relatives of schizophrenic patients, and first-degree relatives of schizophrenic patients with normal sensory gating. The first experiment will study the effects of low and moderate dose scopolamine, a muscarinic antagonist, on P50 auditory gating before and after treatment. Glycopyrrolate, which does not cross into the brain, will be the placebo control. The second experiment will study the effects of 6 mg of oral nicotine on sensory gating, with. bethanechol as a peripheral cholinergic agent to mimic peripheral cholinergic effects without central nervous system (CNS) effects. The third study will use mecamylamine, a ganglionic blocking agent and CNS nicotinic blocker to assess the effect of blocking CNS nicotinic cholinergic transmission on P50 gating.